On Nov. 14, 1997, the U.S. Centers for Disease Control and Prevention (CDC) reported 24 cases of valvular heart disease in women who had been treated with fenfluramine and phentermine were publicly reported. Although valvular lesions were observed on both sides of the heart, a left-sided valve was affected in all cases. The histopathologic features were similar to those observed in carcinoid-induced valvular disease, a serotonin-related syndrome.

Based on these data, the Food and Drug Administration (FDA) issued a public health advisory on July 8, followed by letters from FDA to 700,000 U.S. health-care practitioners and institutions requesting information about any additional similar patients. Subsequently, reports of fenfluramine- or dexfenfluramine-associated valvulopathy increased.

As of September 30, the FDA had received 144 individual, provider-initiated (i.e., “spontaneous”) reports involving fenfluramine or dexfenfluramine, with or without phentermine, in association with valvulopathy (this total included the 24 publicly reported cases. Minimal degrees of regurgitation (i.e., trace or mild mitral regurgitation {MR} or trace aortic regurgitation {AR}) are relatively common in the general population and are not generally considered abnormal.

Therefore, in this analysis, a case of fenfluramine- or dexfenfluramine-associated cardiac valvulopathy was defined as documented AR of mild or greater severity and/or MR of moderate or greater severity after exposure to these drugs. Of the 132 spontaneous reports with complete information, 113 (86%) met the case definition. Of these 113 cases, 111 (98%) occurred among women; the median age of case-patients was 44 years (range: 22-68 years). Of these 113 cases, two (2%) used fenfluramine alone; 16 (14%), dexfenfluramine alone; 89 (79%), a combination of fenfluramine and phentermine; and six (5%), a combination of all three drugs. None of the cases used phentermine alone. The median duration of drug use was 9 months (range: 1-39 months). Overall, 87 (77%) of the 113 cases were symptomatic. A total of 27 (24%) case-patients required cardiac valve-replacement surgery; of these, three patients died after surgery.

Based on data from the five prevalence surveys, FDA requested the voluntary withdrawal of fenfluramine and dexfenfluramine from the U.S. market; on September 15, the manufacturers and FDA announced the withdrawal of the drugs.